Regulatory T Cell Specificity Directs Tolerance versus Allergy against Aeroantigens in Humans.

FOXP3+ regulatory T cells (Tregs) maintain tolerance against self-antigens and innocuous environmental antigens. However, it is still unknown whether Treg-mediated tolerance is antigen specific and how Treg specificity contributes to the selective loss of tolerance, as observed in human immunopathologies such as allergies. Here, we used antigen-reactive T cell enrichment to identify antigen-specific human Tregs. We demonstrate dominant Treg-mediated tolerance against particulate aeroallergens, such as pollen, house dust mites, and fungal spores. Surprisingly, we found no evidence of functional impairment of Treg responses in allergic donors. Rather, major allergenic proteins, known to rapidly dissociate from inhaled allergenic particles, have a generally reduced capability to generate Treg responses. Most strikingly, in individual allergic donors, Th2 cells and Tregs always target disparate proteins. Thus, our data highlight the importance of Treg antigen-specificity for tolerance in humans and identify antigen-specific escape from Treg control as an important mechanism enabling antigen-specific loss of tolerance in human allergy.

Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model.

Introduction: The discovery of immune checkpoints and the development of their specific inhibitors was acclaimed as a major breakthrough in cancer therapy. However, only a limited patient cohort shows sufficient response to therapy. Hence, there is a need for identifying new checkpoints and predictive biomarkers with the objective of overcoming immune escape and resistance to treatment. Having been associated with both, treatment response and failure, LDL seems to be a double-edged sword in anti-PD1 immunotherapy. Being embedded into complex metabolic conditions, the impact of LDL on distinct immune cells has not been sufficiently addressed. Revealing the effects of LDL on T cell performance in tumor immunity may enable individual treatment adjustments in order to enhance the response to routinely administered immunotherapies in different patient populations. The object of this work was to investigate the effect of LDL on T cell activation and tumor immunity in-vitro. Methods: Experiments were performed with different LDL dosages (LDLlow = 50 µg/ml and LDLhigh = 200 µg/ml) referring to medium control. T cell phenotype, cytokines and metabolism were analyzed. The functional relevance of our findings was studied in a HCT116 spheroid model in the context of anti-PD-1 blockade. Results: The key points of our findings showed that LDLhigh skewed the CD4+ T cell subset into a central memory-like phenotype, enhanced the expression of the co-stimulatory marker CD154 (CD40L) and significantly reduced secretion of IL-10. The exhaustion markers PD-1 and LAG-3 were downregulated on both T cell subsets and phenotypical changes were associated with a balanced T cell metabolism, in particular with a significant decrease of reactive oxygen species (ROS). T cell transfer into a HCT116 spheroid model resulted in a significant reduction of the spheroid viability in presence of an anti-PD-1 antibody combined with LDLhigh. Discussion: Further research needs to be conducted to fully understand the impact of LDL on T cells in tumor immunity and moreover, to also unravel LDL effects on other lymphocytes and myeloid cells for improving anti-PD-1 immunotherapy. The reason for improved response might be a resilient, less exhausted phenotype with balanced ROS levels.

Mechanistic basis of co-stimulatory CD40-CD40L ligation mediated regulation of immune responses in cancer and autoimmune disorders.

Generation of an accurate humoral and a cell mediated adaptive immune responsesare dictated by binding of an antigen to a T- and a B-cell receptor, respectively (first signal) followed by ligation of costimulatory molecules (second signal). CD40, a costimulatory receptor molecule, expressed mainly on antigen presenting cells, some non-immune cells and tumors, binds to CD40 ligand molecule expressed transiently on T-cells and non-immune cells under inflammatory conditions. In the past decade, the CD40-CD40L interaction has emerged as an immune-potentiating system that governs and regulates host immune response against various diseases and pathogens, failing of which results in detrimental patho-physiologies including cancer and autoimmune disorders. CD40-CD40L transduces immune signals intracellularly via TRAF-dependent and independent mechanisms and further downstream by different MAPK pathways and transcription factors such as NF-κB, p38 etc. While CD40 signaling pathway through its cognate interaction between B and T cells promotes activation and proliferation of B-cells, Ig class switching, and generation of B cell memory; however, CD40-CD40L interaction involving other APCs and non-immune cells relay distinct cell signaling resulting in production of a variety of cytokines/chemokines and cell adhesion molecules ultimately conferring host defense against pathogen. In cancer and autoimmune disorders, CD40-CD40L interaction is also responsible for aberrant expression of many disease specific markers, class I/II MHC molecules and other co-stimulatory molecules such as B7 and CD28 in cell- and disease-specific manner. In the present review, the current state of understanding about the CD40-CD40L mediated regulation of immune and non-immune cells is presented. The current paradigm is to target CD40 using agonist anti-CD40 mAbs alone or in synergistic combination with chemotherapy in order to harness or confer anti-tumor and anti-inflammatory immunity.